The present invention relates to a novel process for preparing bis(aryl)phosphorohalidates. In particular, this invention relates to a process for preparing bis(2,4-dichlorophenyl)phosphorochloridate, a compound which is required for the synthesis of an enol phosphate intermediate in the manufacture of certain carbapenem antibiotics.
Various processes for the manufacture of bis(aryl)phosphorohalidates have been disclosed in the art. For example, U.S. Pat. No. 4,845,261, which is incorporated herein by reference, discloses a process for preparing bis(2,4-dichlorophenyl)phosphorochloridates wherein the arylphosphorohalidates are produced in one-step procedure performed within a single temperature range utilizing dialkylaminopyridines. Unlike the process of the present invention, U.S. Pat. No. 4,845,261 provides no means of isolating and recovering the valuable phophorodihalidate (monoester) intermediate, and requires an extensive product isolation via crystallization from an organic solvent.
U.S. Pat. No. 3,965,220 discloses a process in which aromatic alcohols and phosphorus halides are allowed to react in the presence of amine catalysts to form various esters of phosphorus acids, including phosphorochloridate estes. Unlike the process of the present invention, however, the process of U.S. Pat. No. 3,965,220 involves a two-stage procedure in which monoesters are formed initially at 85.degree.-135.degree. (preferably 105.degree.) and diesters are then formed, after addition of more phenol, at 130.degree.-165.degree. (preferably 150.degree.). Although the claims of the U.S. Pat. No. 3,965,220 give a temperature range of 85.degree.-165.degree. for preparing "a mono or diester," the specification discloses methods that describe only the range of 85.degree.-135.degree. for monoesters and 130.degree.-165.degree. for diesters.
The process of U.S. Pat. No. 3,965,220 is suitable for the preparation of dihalidates (monoesters) in high yield. However, when bis(aryl)phosphorohalidates are the target, a high temperature, high vacuum distillation is required to separate the desired product from decomposition products and catalysts. Such high temperature distillations frequently result in significant disproportionation and are generally impractical and uneconomical on a commercial scale.
U.S. Pat. No. 3,772,414 discloses a process similar to that of U.S. Pat. No. 3,965,220, except that various ureas instead of an amine are used as catalysts. In U.S. Pat. No. 3,772,414, as in U.S. Pat. No. 3,965,220, an impractical high-temperature distillation is required to purify any diesters.
U.S. Pat. No. 3,689,602 discloses a process in which 2,4-dichlorophenol and phosphorous oxychloride are allowed to react in the presence of heteroaromatic amines such as pyridine. Product isolation in U.S. Pat. No. 3,689,602 is limited to crystallization from organic solvents.
It has been surprisingly discovered that the labor intensive crystallization technique utilized in the art can be supplanted by an efficient, high-vacuum, wiped-film evaporator purification in which the dichloridate intermediate is retrieved as the distillate with the desired product being recovered in a semipure form as the evaporator bottoms.
It is, therefore, an object of the present invention to provide a novel process for the preparation of bis(aryl)phosphorohalidates which provide a means for producing a high-purity product without the need for costly crystallization or impractical high temperature distillation processes previously known in the art. It is also an object of this invention to provide an improved process for the preparation of bis(aryl)phosphorohalidates in higher yields than processes previously known in the art. It is further an object of this invention to provide a process for the preparation of bis(aryl)phosphorohalidate which eliminates air emissions and organic waste.